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. 2025 Jun 15:371:123595.
doi: 10.1016/j.lfs.2025.123595. Epub 2025 Mar 28.

SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity

Neha Saroj  1 , Pankaj Singh Dholaniya  2 , Syed Baseeruddin Alvi  3 , Divya Sridharan  3 , Navisha Soni  3 , Syed Abdullah Ashraf  3 , Ayza Choudhry  3 , Yusuf Ali Ashraf  3 , Sarah Kathleen Mikula  4 , Dinender Kumar Singla  5 , Mahmood Khan  6
Affiliations

SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity

Neha Saroj et al. Life Sci. .

Abstract

Aims: Doxorubicin (Dox) is a potent chemotherapeutic agent, but its use is limited by cardiotoxicity, primarily due to the disruption of Topoisomerase-2 beta (TOP2B) activity. Dexrazoxane (Dex), an FDA-approved cardioprotective drug, alleviates Dox-induced toxicity but lacks heart-specific targeting. This study investigates siRNA-mediated TOP2B knockdown as a more targeted strategy to protect cardiomyocytes from Dox-induced damage.

Materials and methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with siRNA to knock down TOP2B and were then exposed to Dox. We compared the cardioprotective effects of siRNA-mediated knockdown to Dex treatment using cell viability, cell toxicity assay and electrophysiological evaluation was performed using a multielectrode array (MEA).

Key findings: Our results demonstrate that TOP2B silencing significantly decreases apoptosis and improved cell viability, as compared to the Dex treatment. Additionally, electrophysiological assays using a Multielectrode Array (MEA) demonstrated enhanced contractility and conductivity in siRNA-treated hiPSC-CMs. Furthermore, transmission electron microscopy (TEM) data revealed that TOP2B knockdown preserves mitochondrial morphology and sarcomere structure, compared to Dox and Dex-treated groups.

Significance: These findings suggest that siRNA-mediated TOP2B inhibition could provide a safer, more specific approach to mitigate Dox-induced cardiotoxicity.

Keywords: Apoptosis; Cardioprotection; Cardiotoxicity; Dexrazoxane; Doxorubicin; TOP2B; hiPSC-CMs; siRNA knockdown.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mahmood Khan reports financial support was provided by National Heart, Lung, and Blood Institute. Mahmood Khan reports financial support was provided by National Institute of Arthritis and Musculoskeletal and Skin Diseases. Mahmood Khan reports financial support was provided by The Ohio State University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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